Editorial: Prostate Cancer: What We Know and What We Would Like to Know.

Abstract

Cancer research has undergone radical changes over the last few years. The issue today is no longer the amount of molecular, cellular, and clinical information available, but how to handle it. Systems biology is the latest in a series of innovative strategies driven by technological advances that have provided us with a suite of “omics” (1). Technology advancements have enabled comprehensive characterization of genomic, epigenomic, transcriptomic, proteomic, and metabolomic alterations in tumor specimens (2). Despite this continuous progress, prostate cancer remains a major public health problem throughout the world (3). Among men, cancers of the prostate, lung and bronchus, and colon–rectum will account for about 50% of all newly diagnosed cancer (4). Prostate-specific antigen (PSA) is one of the most widely used tumor markers. Although its possible use in early diagnosis or screening PSA has various drawbacks mainly due to its low specificity (5) considering that more than half of the men with PSA over 4.0 ng/ml are negative on initial biopsy (6). A new generation of biomarkers is emerging, consisting of genomic-, serum-, urine-, and tissue-based assays that may supplement PSA testing, or replace it over time (7–9). Although the identification and development of more specific diagnostic biomarkers are considered important, the major focus in translational prostate cancer research is the identification of potential “quantitative variables” to detect clinically significant prostate cancers. As reported by Vlaeminck-Giullem et al. (10), the current dilemma is to specifically distinguish among all prostate tumors the very aggressive high-grade cancers that will become life threatening by developing extra-prostatic invasion and metastatic potential from the indolent cancers that will never modify a patient’s life expectancy. At molecular level, Src and other members of the Src kinase family have been proposed as potential candidates (10). Recently, it has been shown that the activation of Src-dependent intracellular pathways is frequently observed in clinically significant prostate cancer (11). The proto-oncogene tyrosine-protein kinase Src influences some of most important events that accompany tumor progression, including cell proliferation, cell motility, invasion, epithelial-to-mesenchymal transition, resistance to apoptosis, angiogenesis, neuroendocrine differentiation, and metastatic diffusion (11). The particularity of the Src oncogenic action in prostate carcinogenesis is its ability to interfere with the androgen pathway. Through both direct and indirect interaction with the androgen receptor (AR), Src reinforce the proliferative and anti-apoptotic actions of the AR, even in the absence of specific ligands. These molecular mechanisms constitute a solid rationale in favor of the use of Src inhibitors in managing patients with prostate cancer (10, 12). On the other hands, decades of research are now leading to therapeutics that target the molecular mechanisms of the cancer-specific immune response (13). These therapeutics include tumor antigen vaccines, dendritic cell activators, adjuvants that activate innate immunity, adoptive cellular therapy, and checkpoint blockade (13). Another major effort has been in prostate cancer prevention, where blockade of the testosterone metabolism pathway may be a major focus. However, the results of two large randomized, placebo-controlled trials: the prostate cancer prevention trial (PCPT) with finasteride and the reduction by dutasteride of prostate cancer events (REDUCE) trial have fueled controversies on the use of 5α-reductase inhibitors (5-ARI). Finasteride and dutasteride are among the agents used to target the androgen–AR axis to prevent the development and/or progression of prostate cancer, as summarized by Kosaka et al. (14). In particular, 5-ARIs have been shown to play a potential role in preventing clinical progression among men with low-risk prostate cancer on active surveillance. However, in light of the US Food and Drug Administration recommendation against 5-ARIs for primary chemoprevention, these findings should be interpreted with caution (3, 15).